title: Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer.
abstract: OBJECTIVE
  To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer.
  
  
  METHODS
  Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates.
  
  
  RESULTS
  The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%).
  
  
  CONCLUSIONS
  Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.
authors.affiliation: Department of Haematology/Oncology and Tumor Immunology, Robert-Rössle-Klinik, Berlin, Germany. koehne@rrk-berlin.de
authors.forename: C H
authors.initials: CH
authors.lastname: Köhne
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
authors.forename: H
authors.initials: H
authors.lastname: Wilke
authors.forename: C
authors.initials: C
authors.lastname: Käufer
authors.forename: R
authors.initials: R
authors.lastname: Andreesen
authors.forename: U
authors.initials: U
authors.lastname: Ohl
authors.forename: U
authors.initials: U
authors.lastname: Klaasen
authors.forename: M
authors.initials: M
authors.lastname: Westerhausen
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.forename: G
authors.initials: G
authors.lastname: Schott
authors.forename: A
authors.initials: A
authors.lastname: Harstick
authors.forename: J
authors.initials: J
authors.lastname: Bade
authors.forename: A
authors.initials: A
authors.lastname: Horster
authors.forename: U
authors.initials: U
authors.lastname: Schubert
authors.forename: H
authors.initials: H
authors.lastname: Hecker
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.forename: H J
authors.initials: HJ
authors.lastname: Schmoll
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins; D015996:Survival Rate
chemical_list: D000964:Antimetabolites, Antineoplastic; D007155:Immunologic Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D002955:Leucovorin; D005472:Fluorouracil